New integrative biodemographic and gerontological frameworks, a better etiologic understanding of both disease and geriatric conditions, and technological advances in minimally-invasive specimen collection are resulting in the incorporation of increasingly broad arrays of biological markers into population research. This career award will draw on these advances to examine impairment in the regulation of interacting physiologic (e.g., organ) systems. Such impairment is theorized to reflect decreased resilience to social and physical challenges. We hypothesize that 1) reaching a critical mass of impaired regulation among physiologic systems accelerates the risk of frailty, disability, and mortality; 2) that impaired regulation among physiologic systems, as well as frailty, disability and mortality, tend to emerge earlier in the life course in persons who are chronically subjected to high levels of environmental challenge; and 3) that observed increases in life expectancy represent secular trends in improved health and later onset of impaired regulation among physiologic systems and outcomes in more recent birth cohorts, relative to older birth cohorts, and that this delay will be less in those with greater exposure to challenges, lower socioeconomic status, and Americans from underrepresented minority groups compared to white Americans. I will use data from five major population-based studies and achieve my goal in three steps that comprise my aims. The steps are to determine: when and how impairment in regulation emerges, how it is associated with potential sequelae, and variations across vulnerable subgroups (Aim 1); whether impaired physiologic regulation is affected by challenges in the environment (Aim 2); and how individual and environmental factors jointly shape the health and function of older adults in the U.S., both individually and at the population level (Aim 3). During the award period I will obtain specialized training in physical environment challenges facing older adults, advanced statistical methods, and biological, clinical, and laboratory content. This training will enable me to continue my development into an independent researcher focused on understanding the biological pathways that link social and physical challenges to health among community-dwelling older adults, and the significance of these pathways for changes in population health.